1. Field of the Invention
This invention relates to an iontophoretic device structure of the dissolution-on-use type which is useful for transdermal or transmucosal delivery of drugs or biologically active substances into living bodies in the medical field. It is to be noted that the term "drugs and biologically active substance" used herein may be sometimes referred to simply as "drugs".
2. Prior Art
Iontophoresis is a system of promoting transdermal or transmucosal absorption by the use of electricity as an external stimulation. In the system, the transmittance of the molecules of a drug or medicine through a skin barrier is promoted on the basis of the principle that, in the electric field produced between the anode and the cathode by application of an electric current, positively charged molecules of the drug are moved from the anode toward the cathode and negatively charged molecules are moved from the cathode toward the anode Journal of Controlled Release, Vol. 18, 213-220 (1992), Advanced Drug Delivery Review, Vol. 9, 119 (1992), and Pharmaceutical Research, Vol. 3, 318-326 (1986)!.
Recent advances of synthetic technologies and genetic engineering lead to pure and mass production of naturally-occurring peptides or proteins, those peptides or proteins wherein their amino acid compositions are changed, or chemically modified derivatives thereof. The applications of these substances as drugs have now been expected. On the other hand, however, as studies on these peptides or proteins are in progress, it has been made clear that the diversity of biological activities of the peptides or proteins are physiologically controlled by the minute and complicated in vivo kinetics. In order to permit a peptide or protein to show the maximum medical efficacy on a specific disease and to suppress its side effect to a minimum, there has been required a system which enables one to strictly control the dosage of the peptide or protein. For instance, calcitonin has the capability of keeping the amount of bone from being reduced by suppression of the absorption of bone and is thus employed for the treatment of osteoporosis or Paget's disease. However, an excessive administration brings about a side effect such as inappetence. In addition, for the improvement of the treating effect, it is essential to repeatedly administer the peptide or protein.
It is known that some types of peptides develop different medical efficacies depending on the manner of administration thereof. For instance, parathormone exhibits different actions which are contrary to each other, i.e. a bone absorption-promoting action and bone formation-promoting action. When intravenously injected at a given rate, this hormone develops the bone resorption-promoting action, whereas the bone formation-promoting action is strongly developed by frequent administration through subcutaneous injection. In order to employ the parathormone as a drug for treating osteoporosis while expecting its bone formation-promoting action, the preparation thereof has to be of the pulse-release type, not of the slow release type. However, it is known that such a biologically active peptide or protein is usually decomposed in a digestive fluid in the gastrointestinal tract, or is hydrolyzed with a hydrolase present in the digestive tract walls, and thus is poor in an absorption efficiency. This means that any satisfactory medical efficacy cannot be expected when these biologically active peptides or proteins are orally administered. Thus, the usual practice is to administer them through injection. However, an injection causes a great pain to a patient, and is hence unsuitable for self administration, thus imposing a great burden on the patient. This will become so much the worse for the case where repeated, continuous administration is required, for example, as in the case of the afore-indicated calcitonin or parathormone.
In the pharmaceutical or medical field, attention has now been paid to iontophoresis which is a novel drug delivery system responsible for the administration of such biologically active peptides or proteins, and extensive studies have been made thereon. More particularly, if drugs which have conventionally been able to be administered only as an injection can be self-administered by a patient himself according to the iontophoresis, this will clear the way for treatment at home. The precise control in time of application of an electric current permits a desired absorption pattern to be created. Especially, in the supplemental therapy of an endogenous compound, it is conceivable to realize more effective therapy with the compound while taking the circadian rhythm of a living body into account.
On the other hand, extensive studies have been made on the devices to be employed for the iontophoresis so as to have drugs transdermally absorbed in an efficient manner. The device has a fundamental structure which includes a layer containing an electrolyte, and a layer comprised of at least a partially ionized drug. A porous membrane such as a non-woven fabric is used, for example, as the drug layer. During use, a potential is applied via an electrode which has been preliminarily disposed in the electrolyte layer or on the upper surface thereof, so that the drug is delivered to a living body from the surface such as of the porous membrane via the skin.
However, such devices have a number of defects to be overcome. For instance, Japanese Laid-open Patent Application No. 63-502404 sets out a device which includes a cavity containing an electrolyte, another cavity containing at least a partially ionized drug, and an ion exchange membrane provided between the cavities and capable of suppressing the movement of competitive ions produced from electrodes. In U.S. Pat. Nos. 5,250,022 and 5,362,308, there are proposed devices which include a housing provided with a first chamber accommodating an electrolyte therein and a second chamber accommodating an ionized drug, wherein the first chamber comprises an ion exchange resin for suppressing the movement of competitive ions produced from electrodes and also a semi-permeable membrane for preventing the drug from being reversely diffused.
However, these devices commonly have the problem that when dried, the ion exchange membrane cracks, with the great possibility that the ion selectivity lowers considerably. Avoiding the problem leads to the disadvantage that the steps of fabricating the devices become more complicated. In both United States Patents, the ion exchange resin and the semi-permeable membrane are employed in the first chamber. Where the semi-permeable membrane and the first chamber portion are poorly bonded, there is the apprehension that the drug is reversely diffused through the gap formed between the membrane and the first chamber portion. Moreover, as having set out hereinabove, these devices essentially require an additional ion exchange membrane, or the provision of an ion exchange resin and a semi-permeable membrane, with their structures becoming complicated.
On the other hand, where a drug contained in devices is in the form of a solution and is thus unstable and, especially, where the drug consists of a biologically active peptide or protein, it undergoes a non-reversible change, such as hydrolysis, association or coagulation, in the solution. This results in the lowering of activity during storage or prior to the use of the device. In order to overcome this problem, it is convenient to use a device of the dissolution-on-use type wherein a drug is preserved or kept in a dry condition. For instance, WO93224177 sets forth a device of the type which comprises a reserver layer containing an electrode and a drug, both in a dried condition, and a water supplying layer disposed above the reserver layer wherein when a tab provided between both layers is removed, the drug is dissolved. Moreover, Japanese Laid-open Patent Application No. 63-102768 sets out a device wherein capsules for water supplement are incorporated into an electrode and a drug layer in a dry condition.
However, these devices have such a special structure capable of holding the liquid compartment that the device structure becomes complicated as a whole. In addition, when using an ion exchange membrane having an ion selective function or a combination with an ion exchange resin, the resultant device becomes more complicated in structure. Hence, the fabrication of these devices requires correspondingly a greater number of steps, presenting the problem that the fabrication costs become very high.
Aside from the above-stated problems involved in the hitherto known iontophoretic devices, we found through observation of this type of device having been actually made by us that prior to the use of the device, the reverse diffusion of a drug and the ionization of an electrode-constituting metal were observed. Not only the reverse diffusion and the ionization impeded the performance of the device on use, but also the metal ions arrived at a skin at an early stage where they were absorbed in the living body, thereby causing damages thereto. Additionally, it was also found that as the dissolved-out metal ions moved, they served to impede the movement of a drug to be delivered from the device and the transdermal absorption thereof.
In order to solve the problems of the prior art iontophoretic devices, we made intensive studies and investigations on this type of device. As a result, it was found that when the device is arranged to be of the dissolution-on-use type wherein a hydrophilic, polymeric gel layer dispersing an ion exchange resin therein is provided between a non-polarizable electrode and a drug layer, metal ions can be specifically prevented from being dissolved out from the non-polarizable electrode, and the reverse diffusion of a drug prior to the use of the device can be appropriately prevented. By this, the device ensures the long-term capability of an electric current being applied thereto so that the drug can be reproducibly, transdermally administered at high bioavailability. The invention has been accomplished based on the above findings.